BOSTON - April 18, 2004 - Researchers at Massachusetts General
Hospital (MGH) have developed a way of identifying promising new
drugs that may get around a major challenge in drug discovery. In
the May issue of Nature Biotechnology the team from the MGH Cardiovascular
Research Center (CVRC) describes using an animal model to screen
for a compound that suppresses a serious genetic mutation. Their
success did not rely on first identifying a molecular target for
the new drug, something that is a key bottleneck in current procedures.
The study is being released today on the journal's
website.

"Currently most drugs are designed to act on a specific protein,
but for most diseases we still don't know what the protein targets
should be," says Randall Peterson, PhD, of the MGH CVRC, the
paper's lead author. "This is a totally different approach
that shows how, without knowing the best target, you can screen
for drugs that could reverse a disease and in the process learn
something new about the underlying biology."

The researchers started with embryos of zebrafish - a tiny tropical
fish used as a model of vertebrate development - with a mutation
called gridlock, which prevents the correct development of the circulatory
system in the lower portion of the body. A panel of these embryos
was exposed to a very diverse library of small molecules - 5,000
in all - to see if any would prevent expression of the gridlock
mutation. Two similar molecules were identified that suppressed
the mutation, allowing the embryos to develop normally. The one
that appeared more powerful, called GS4012, was chosen for further
study.

The gridlock-suppressing effects of GS4012 were found to vary with
dosage, and no vascular abnormalities were seen at the doses studied.
Application of the compound appeared to be most effective at a developmental
stage right before and during the formation of major vascular structures.
Further experiments showed that GS4012 appears to promote the activity
of the angiogenesis factor VEGF and also induces the development
of vascular networks in cultured human vascular cells.

"We had a strain of fish with a very specific arterial defect,
and although we knew which gene was responsible, there was a lot
we didn't know about the molecular processes disrupted by that mutation,"
says Peterson "We were able to find a compound that could reverse
the mutation and are hopeful that it will provide fundamental new
insights into vascular development and disease.

"While this molecule may eventually have clinical application
in promoting vascular growth after heart attack, stroke or injury,
this new way of identifying potential new drugs may have an even
greater impact," he adds. In addition to further studying the
mechanism behind the action of the gridlock suppressors they identified,
the research team hopes to apply this new drug-discovery approach
to other diseases.

In addition to Peterson, an assistant professor of Medicine at Harvard
Medical School, the research team includes senior author Mark Fishman,
MD, formerly director of the CVRC and chief of MGH Cardiology, now
president of the Novartis
Institutes for BioMedical Research; Stanley Shaw, MD, PhD, Travis
Peterson, David Milan, MD, and Calum MacRae, MB, ChB, of the MGH
CVRC; Tao Zhong, PhD, of Vanderbilt School of Medicine; and Stuart
Schreiber, PhD, of Howard Hughes Medical Institute at Harvard University.
The research was supported by grants from the National Institute
of Health, the Ned Sahin Research Fund for Supporting Developmental
Plasticity, and a research agreement with the Novartis Institutes
for BioMedical Research.

Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of more than $400 million
and major research centers in AIDS, cardiovascular research, cancer,
cutaneous biology, medical imaging, neurodegenerative disorders,
transplantation biology and photomedicine. In 1994, MGH and Brigham
and Women's Hospital joined to form Partners HealthCare System,
an integrated health care delivery system comprising the two academic
medical centers, specialty and community hospitals, a network of
physician groups, and nonacute and home health services.